Essential role for premature senescence of myofibroblasts in myocardial fibrosis
Open accessAbstract
Background Fibrosis is a hallmark of many myocardial pathologies and contributes to distorted organ architecture and function. Recent studies have identified premature senescence as a regulatory mechanism of tissue fibrosis, but its relevance in the heart remains to be established.Objectives This study investigated the role of premature senescence in myocardial fibrosis.Methods Murine models of cardiac diseases and human heart biopsies were analyzed for characteristics of premature senescence and fibrosis. Loss-of-function and gain-of-function models of premature senescence were used to determine its pathophysiological role in myocardial fibrosis.Results Senescence markers p21(CIP1/WAF1), senescence-associated ß-galactosidase (SA-ß-gal), and p16(INK4a) were increased 2-, 8-, and 20-fold (n = 5 to 7; p < 0.01), respectively, in perivascular fibrotic areas after transverse aortic constriction compared with sham-treated control subjects. Similar results were observed with cardiomyocyte-specific β1-adrenoceptor transgenic mice and human heart biopsies. Senescent cells were positive for platelet-derived growth factor receptor-α, vimentin, and α-smooth muscle actin, specifying myofibroblasts as the predominant cell population undergoing premature senescence in the heart. Inactivation of the premature senescence program by genetic ablation of p53 and p16(INK4a) (Trp53(-/-)Cdkn2a(-/-) mice) resulted in aggravated fibrosis after transverse aortic constriction, when compared with wild-type control subjects (49 ± 4.9% vs. 33 ± 2.7%; p < 0.01), and was associated with impaired cardiac function. Conversely, cardiac-specific expression of CCN1 (CYR61), a potent inducer of premature senescence, by adeno-associated virus serotype 9 gene transfer, resulted in ∼50% reduction of perivascular fibrosis after transverse aortic constriction, when compared with mock- or dominant-negative CCN1-infected control subjects, and improved cardiac function.Conclusions Our data establish premature senescence of myofibroblasts as an essential antifibrotic mechanism and potential therapeutic target in myocardial fibrosis.
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Cellular senescence has roles in limiting myocardial and liver fibrosis, promoting skin healing, and in embryonal development.
“Experimental evidence shows that cellular senescence has roles in limiting myocardial206 and liver207 fibrosis, promoting skin healing,82 as well as in embryonal development,208 which have to be considered.”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [206]
The studies showing roles of senescence in limiting myocardial and liver fibrosis, promoting skin healing, and embryonal development focused on acute organ injury, not chronic processes such as atherosclerosis.
“However, these studies focused on the function of senescence in acute organ injury, not in chronic processes such as atherosclerosis.”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [206]
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- Authors
- Meyer, K., Hodwin, B., Ramanujam, D., Engelhardt, S., & Sarikas, A.
- Affiliations
- German Centre for Cardiovascular Research (DE)
- Technical University of Munich (DE)
- Corresponding author
- Sarikas, Antonio
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 67
- Issue
- 17
- Pages
- 2018-2028
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2343545062
- Cited by
- 247
- References
- 41
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 23 · 2023: 36 · 2022: 28 · 2021: 29 · 2020: 38 · 2019: 18 · 2018: 20 · 2017: 8 · 2016: 6
- FWCI
- 14.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- University of Illinois at Urbana-Champaign
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- premature senescence, myocardial fibrosis, myofibroblasts, p16INK4a, p53, CYR61, transverse aortic constriction, beta1-adrenergic receptor, senescence-associated β-galactosidase, antifibrotic mechanism, gene therapy, cardiac function
- MeSH terms
- Actins, Dependovirus, Animals, beta-Galactosidase, Fibrosis, Humans, Myocardium, Vimentin, Tumor Suppressor Protein p53, Cellular Senescence, Gene Transfer Techniques, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p16, Receptor, Platelet-Derived Growth Factor alpha, Cyclin-Dependent Kinase Inhibitor p21, Cysteine-Rich Protein 61, Myofibroblasts
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